Compositions and methods to detect GluA1 in brain and to identify the presence of GluA1-mediated PTSD

Abstract

The present invention provides compositions and methods for detecting GluA1, as a subunit protein and/or as a GluA1-containing, GluA2-lacking AMPAR complex. The invention further provides composition and methods for detecting and/or diagnosing PTSD. The invention further relates to compositions that can be detected using radiological imaging techniques, and processes for performing such imaging techniques using the compositions, to identify elevated GluA1 expression or activity in a subject, which is a biological marker of PTSD.

What is claimed is: 
     
       1. A radiolabeled composition comprising at least one ligand of a GluA1 or a ligand of a GluA1-containing, GluA2-lacking AMPAR labeled with a radioactive isotope, wherein the radiolabeled composition comprises a compound of following structure: 
       
         
           
           
               
               
           
         
       
       wherein the F is an [18F] isotope. 
     
     
       2. A method of detecting GluA1 levels, or GluA1-containing, GluA2-lacking AMPAR levels, in a portion of a brain of a subject, comprising:
 administering to the subject a first amount of a radiolabeled composition as set forth in  claim 1  comprising a ligand of GluA1 or a ligand of a GluA1-containing, GluA2-lacking AMPAR effective for detection of the radiolabeled composition in the portion of the brain of the subject using radiological imaging; and 
 determining or quantifying, by the radiological imaging of the radiolabeled composition in the portion of the brain of the subject, GluA1 subunit density or GluA1-containing, GluA2-lacking AMPAR density in the portion of the brain of the subject. 
 
     
     
       3. The method of  claim 2 , wherein the portion of the brain of the subject is an amygdala. 
     
     
       4. The method of  claim 3 , wherein determining or quantifying GluA1 subunit density or GluA1-containing, GluA2-lacking AMPAR density in the amygdala of the subject comprises detecting or visualizing radioactive emissions of the radiolabeled composition in the amygdala after administration. 
     
     
       5. The method of  claim 3 , wherein determining or quantifying GluA1 subunit density or GluA1-containing, GluA2-lacking AMPAR density in the amygdala of the subject comprises:
 creating at least one image of a brain of the subject using positron emission tomography (PET) or single-photon emission computed tomography (SPECT); and 
 determining or quantifying from the at least one image a GluA1 subunit density or a GluA1-containing, GluA2-lacking AMPAR density in the amygdala of the brain of the subject based at least in part upon an amount of the radiolabeled composition detected in the at least one image, so as to detect GluA1 protein levels, or GluA1-containing, GluA2-lacking AMPAR levels, respectively, in the amygdala of the subject. 
 
     
     
       6. The method of  claim 5 , wherein the at least one image of the brain is created between 15 minutes and 3 hours following administration of the radiolabeled composition. 
     
     
       7. The method of  claim 3 , further comprising comparing the GluA1 subunit density or GluA1-containing, GluA2-lacking AMPAR density in the amygdala of the subject with a predetermined baseline level, wherein a density greater than the predetermined baseline level indicates Post-Traumatic Stress Disorder (PTSD) in the subject. 
     
     
       8. The method of  claim 7 , wherein a density in the amygdala that exceeds the predetermined baseline level by at least a threshold amount indicates Post-Traumatic Stress Disorder (PTSD) in the subject. 
     
     
       9. The method of  claim 7 , wherein the predetermined baseline level is determined by:
 a. performing the imaging detection process on a first plurality of subjects known not to be suffering from PTSD; 
 b. determining first respective amygdalar GluA1 levels or GluA1-containing, GluA2-lacking AMPAR levels in each of the first plurality of subjects; 
 c. computing a first normalized average of the first respective amygdalar GluA1 levels or GluA1-containing, GluA2-lacking AMPAR levels; 
 d. performing the imaging detection process on a second plurality of subjects known to be suffering from PTSD; 
 e. determining second respective amygdalar GluA1 levels or GluA1-containing, GluA2-lacking AMPAR levels in each of the second plurality of subjects; 
 f. computing a second normalized average of the second respective amygdalar GluA1 levels or GluA1-containing, GluA2-lacking AMPAR levels; and 
 g. determining as the predetermined baseline level an amygdalar GluA1 level or GluA1-containing, GluA2-lacking AMPAR level based at least in part upon the first normalized average and the second normalized average. 
 
     
     
       10. The method of  claim 2 , wherein the radiolabeled composition comprises an [ 18 F] radioisotope. 
     
     
       11. The method of  claim 2 , wherein the radiolabeled composition comprises a saline or ethanol solution. 
     
     
       12. The method of  claim 2 , wherein the radiolabeled composition is administered to the subject via a nasal spray, inhalation, or injection into the bloodstream, in a manner effective to enter the amygdala of the subject. 
     
     
       13. The method of  claim 2 , wherein the first amount of the radiolabeled composition administered to the subject comprises a mass dose of the radiolabeled composition in a range of 0.0001 pg to 1 ng per kg of body weight of the subject. 
     
     
       14. The method of  claim 2 , wherein an effective radiation dose equivalent associated with the first amount of the radiolabeled composition administered to the subject falls in a range of 1 to 100 μSv. 
     
     
       15. A method of treating Post-Traumatic Stress Disorder (PTSD) in a subject, comprising:
 a. receiving information indicating a detection of elevated levels of GluA1, either alone as a subunit protein or in GluA1-containing, GluA2-lacking calcium permeable AMPAR complexes in an amygdala of the subject, wherein the detection has been obtained by:
 i. administering to the subject an amount of a radiolabeled composition as set forth in  claim 1  comprising at least one radiolabeled ligand of GluA1 or comprising at least one radiolabeled ligand of a GluA1-containing, GluA2-lacking AMPAR, the amount of the radiolabeled composition effective to detect the radiolabeled composition in the amygdala of the subject using positron emission tomography (PET) or single-photon emission computed tomography (SPECT), is in a range of 0.0001 pg to 1 ng per kg of body weight of the subject or an effective radiation dose equivalent associated with the amount of the radiolabeled composition administered to the subject falls in a range of 1 to 100 μSv; 
 ii. determining or quantifying GluA1 levels or GluA1-containing, GluA2-lacking AMPAR levels in the amygdala of the subject; and 
 iii. determining or quantifying GluA1 levels or GluA1-containing, GluA2-lacking AMPAR levels exceed a predetermined baseline level; and 
 
 b. administering to the subject an amount of a treatment composition effective to treat PTSD. 
 
     
     
       16. The method of  claim 15 , wherein the respective amount of the treatment composition is effective to reduce GluA1 expression levels or GluA1-containing, GluA2-lacking AMPAR expression levels in the amygdala of a subject. 
     
     
       17. The method of  claim 15 , wherein the respective amount of the treatment composition is effective to inhibit receptor function of GluA1-containing, GluA2-lacking AMPARs in the amygdala of the subject. 
     
     
       18. The composition of  claim 1 , wherein the radiolabeled detector is suitable as a radiolabeled tracer in a nuclear imaging detection process.